Abstract Myeloma accounts for almost 14% of all hematologic cancers and is essentially incurable. Recent studies have documented increasing evidence for an inherited genetic basis for multiple myeloma (MM). Genome-wide association studies have identified common variants in transcriptional regulators and tumor suppressors associated with risk of sporadic MM and we have recently identified presumed deleterious germline variants in a group of familial cases following sequencing. As described in this application, we have already performed exome sequencing of 934 probands and affected relatives. However, systematic analyses of germline genetic alterations in sporadic and familial MM have not been performed to validate the interesting candidate genes from these exome data. In this proposal, we will build on our prior work and pre-existing genomic data to prioritize, identify and validate novel candidate genes conferring susceptibility to MM. We also undertake a meta-analysis with an African American study to understand commonality and heterogeneity of risks. These studies represents the first systematic approach to understand the germline genetic variations in a large group of well characterized MM cases and controls towards identification of moderate and high risk genetic variants that predispose to MM, which will be of utility in prevention, diagnosis, and modification of treatment of MM. Together, these studies will provide critical new insights into the genetic basis of MM and lymphoid malignancies.